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Natural history of cervical neoplasia: Overview and update
Natural history of cervical neoplasia: Overview and update Nancy Kiviat, MD
Seattle, Washington Current cervical cancer control strategies and specifically, the screening and treatment policies that have been used during the past 30 years, are based on an understanding of the natural history of cervical neopiasia that does not take into account the important role of human papiltomavirus in cervical cancer pathogenesis. This survey presents a review of new data on the causes of cervical cancer and the role of human papillomavirus and recommends the integration of these data. Incorporation of new information on the role of human papillomavirus as the causative agent of most cervical cancers will allow the design of more efficient and more cost-effective strategies for cervical cancer control. (Am J Qbstet Gynecol 1996;175:1099-104.)
During the past 50 years mortality rates of cervical cancer have dramatically decreased. ~Although it is likely that some decline in mortality- rates of cervical cancer occurred before the establishment of public health programs focused on cervical cancer control, it has been well documented that the greatest decreases in mortality rates of cervical cancer occurred at specific sites subsequent to implementation of cervical cancer screening. ~The development of current control strategies for cervical cancer and specifically, screening and treatment policies that have been used during the past 30 years, are based on a view of the natural history of cervical neoplasia that predates the discovery of the importance of h u m a n papillomavirus (HPV) in cervical cancer pathogenesis. Although our current approach to cervical cancer control has been successful in lowering mortality rates of cervical cancer, it is widely acknowledged to be inefficient and costly. Recent studies discussed herein, which demonstrate the central role of HPV in both benign and malignant cervical disease, have raised questions about the validity of our currently accepted beliefs about the natural history of lesions classified as "dysplasia" or "cervical intraepithelial neoplasia." If we can incorporate what has been learned about HPV and its relationship to cervical disease into cervical cancer control policies, we can increase the cost-effectiveness of such programs. Current cervical c a n c e r control strategies
Cervical cancer control programs are based on the belief that invasive cervical cancer arises from more treatable localized lesions, termed "carcinoma in situ" or "cervical intraepithelial neoplasia grade 3" (CIS/CIN 3). These lesions, which are thought to be the immediate
From the Departmenl of Patholog)~, University of Washington. Reprint requests: Nancy Kiviat, MD, Department of Pathology, University of Washington, HPV Research Group, 6 Nickerson St., Suite 310, Seattle, WA 98109. Copyrigkt © 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/0/76602
precursors of invasive cervical cancel, can be easily removed to prevent the development of invasive disease. Therefore the primary aim of cytologic screening has been identification of women with CIS/CIN 3 (term consistent with "high-grade squamous intraepithelial lesions" (SIL) or CIS when identified on Papanicolaou smears). In addition, during the past 30 years, it has been widely accepted that CIN 1, CIN 2, and CIN 3 represent progressive successive stages in the development of invasive cervical cancer (see "Historical and Scientific Basis" section below). Therefore cytologic screening has also focused on identification of women with CIN 1 and CIN 2. Another cervical epithelial lesion that many feel may have malignant potential is termed "squamous atypia" (when identified histologically) or "atypical squamous cells of uncertain significance" (ASCUS) if detected on Papanicolaou smears, z Because this lesion is characterized by less marked cellular abnormalities than are CIN lesions, it has been suggested that it represents a still earlier stage in cervical cancer pathogenesis. Currently all women who have cytologic evidence of highgrade SIL or its equivalent, the majority of women with low-grade SIL (the cytologic equivalent of CIN 1), and those with repeated ASCUS or atypia are referred for colposcopy and biopsy. Women in whom a biopsy specimen confirms the presence of CIN 2-3 and many of those with biopsy" confirmed CIN 1 then undergo ablation of transformation zone epithelium. The rationale for follow-up and treatment of women with repeated atypia and CIN 1 is the belief that "squamous atypia," CIN 1, CIN 2, and CIN 3/CIS represent successive progressive stages in the pathogenesis of cervical cancer. Shortcomings of current cervical c a n c e r control strategies
Screening for and treatment of the lesions described previously have clearly led to a decrease in mortality rates of cervical cancer. However, this strategy is not without problems. It is well established that ablation of the trans1099
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formation zone is not completely without morbidity,e~8 Furthermore, identification a n d treatment of ASCUS, CIN 1, and CIN 2, in addition to CIN 3 and CIS, are costly. For example, the prevalence of CIN 1 has been reported to be as high as 13% among young sexually active women, 9 making this an extremely common lesion. Costs for colposcopy and biopsy range from $150 to $750, whereas ablative therapy ranges from $200 to over $2000 depending on the modality used (survey of 18 centers in the United States by A. Herbst? ° Assuming (conservatively) that only 1% of women between 15 and 49 years old have low-grade SIL, that all are referred for colposcopy and biopsy at a cost of $200, and that 50% are treated, the annual cost of such an approach would exceed 200 million dollars. Furthermore, atypia or ASCUS is found in 10% to 30% of Papanicolaou smears depending on the population examined. If one assumes that only 15 % of women with ASCUS require repeat cytologic studies at a cost of $30 and that 30% of these women will subsequently undergo colposcopy and biopsy, this would result in at least an additional $300 million being spent annually. The figures suggest that such an approach may not be justified. To determine the validity of this approach, we need to examine more closely the historical perspective and scientific basis for current policies.
Historical and scientific basis for current management of strategies for women with abnormal cytologic and histologic findings Modern studies of the pathogenesis of cervical cancer date from the turn of the century when a few investigators undertook systematic microscopic examination of the uteri of women with cervical cancer] ~-13These early investigators noted that the architecture of the cervical epithelium appeared intact in areas adjacent to invasive tumors. The normal epithelial cells in such areas, however, were frequently replaced by a population of cells whose morphologic features resembled the cells seen within the invasive tumor mass. It was hypothesized that such lesions were precursors of invasive cancers and therefore such lesions were termed "carcinoma in situ." The logical extension of this hypothesis was that women in whom such lesions were present but who did not have invasive cancer would develop invasive cancer if such tissue was not removed. As the idea that untreated CIS had a high likelihood of progression to invasive cancer quickly gained popularity, it soon became unethical to carry out studies to actually test this hypothesis. Therefore todaywe know little about the true risk of development of invasive cancer associated with untreated CIS. What little data exist comes primarily from a small series of women with CIS who inadvertently were not treated. In addition, in several series undertaken before ablative treatment became the accepted standard of care, women repeatedly underwent biopsies rather than given definitive treat-
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ment.14. 15 Review of available data suggests that, if left untreated, CIS would regress in approximately 10% to 30% of women and that from 12% to 70% would develop invasive disease within the span of a normal lifetime? ~-18 After acceptance of the concept of CIS by the medical community, pathologists began to document the existence of other cervical abnormalities, now referred to as CIN and squamous atypia. These lesions are made up of a population of more differentiated cells than those seen in CIS. On the basis of their less striking morphologic changes and the fact that they appeared to be present more frequently in women without cervical cancer, it was hypothesized that they represented earlier stages in cervical cancer pathogenesis than did CIS. 19' 20 How strong is the data supporting the now-popular view that these lesions (CIN 1, CIN 2, and CIN 3) represent a morphologic and biologic continuum of progressive consecutive stages in the development of invasive cancer? Numerous studies have described the risk of progression of CIN 1 and CIN 2 to CIS. Differences in study entry criteria, length of follow-up, follow-up procedures (e.g., repeated biopsy vs follow-up by Papanicolaou smear alone), and statistical methodology make comparisons of these studies difficult. However, most studies suggest that from 10% to 15% of women with CIN 1 who are followed without biopsy will subsequently develop CIN 2-3. At least 60% will have smears that regress to normal, and approximately 30% will have persistence of CIN 1.1e~I8'21, 22 The rate of regression appears even higher when considering those women who have had only a single Papanicolaou smear showing low-grade SIL on study entry. However, in contrast to the overwhelming majority of natural history studies, the results from one of the first large studies of this type reported that more than 50% of women with low-grade SIL developed CIN 3 within 5 years. 2~-25Furthermore, almost no regression occurred in this later study. On the basis of this study Barron and Richart proposed the "cervical intraepithelial neoplasia" classification system. This classification system has served as the basis for the diagnosis and clinical management of cervical disease in the past 20 years. Inherent in this classification system is the belief that the various morphologic changes observed on Papanicolaou smears and biopsy represented successive (increasingly abnormal) stages in the pathogenesis of cervical cancer. To emphasize that these lesions represent a continuum in development of malignancy, they were collectively termed "cervical intraepithelial neoplasia" grades 1, 2, and 3. 25 Most other natural history studies did not support this hypothesis, but had in fact demonstrated that low-grade SIL was generally a benign lesion. Despite this fact, the idea that untreated CIN 1 had a high probability of becoming invasive cancer has had widespread acceptance and served as the rationale for aggressive management of these lesions. The markedly higher rate of progression
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and lack of regression seen in the Richart and several other more recent studies, 26as compared with most other studies, is partly related to study entry criteria. Richart and Baron required that study participants have multiple previous smears showing CIN 1. Because most regression of CIN 1 normally occurs during the first year or two after an initial cytologic detection of CIN 1, such entry c r i t e r i a inadvertently selected for those women who were most ]ikely to have lesions that would not regress. Therefore although the results of the Richart and Barron study may provide insights into the natural history of CIN 1 lesions that have persisted for at least a 1-year period, this study tells us little about the natural history of most CIN 1 lesions. Other studies that did not have similar entry criteria provide more valuable information about the appropriate clinical management of women with incident CIN or atypia. Furthermore, some of the women classified to have CIN 1 according to the Okagaki cytologic classification s y s t e m 27 used in the Richart and Barron study would have been assigned a diagnosis of CIN 3 by the World Health Organization system used in most other studies. In summary, most available data suggest that CIN 1 lesions and atypias do not generally progress.
HPV infection and cervical pathology HPV infection of the genital tract has now been convincingly demonstrated to be the most common sexually transmitted viral infection in the United States. 2s Genital warts have long been known to occur on the vulva, vagina, cervix, penis, and anus29; however, only recently has it become clear that a n u m b e r of different sexually transmitted v i r u s e s a r e responsible for all of these lesions. Furthermore, it is now apparent that the flat lesions seen with the aid of a colposcope after application of acetic acid (which were traditionally classified by colposcopists as consistent with CIN) are related to the typical genital warts seen on the vulva and penis. All these lesions a r e manifestations of ttPV infection. Lastly, we have learned that the microscopic manifestations of HPV infection a r e among those morphologic changes normally classified by pathologists as consistent with CIN. Traditional techniques for culturing viruses cannot be used for identification of HPV infection as replication of HPV with complete capsid formation occurs only in terminally differentiated squamous cells. Therefore other techniques for diagnosis have been used including clinical, colposcopic, and microscopic examination. More recently, HPV DNA has been detected by hybridization with or without prior amplification of specific types of HPV DNA. s° The absence of a culture system has made development of a serologic assay extremely difficult; as a result, we have no estimate of the lifetime risk of exposure to these viruses. Only with the recent development and application of newer assays have we gained a true appreciation of the high prevalence of infection with the sexually
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transmitted types of this virus. ~s The advantages and limitations of specific assays for detection of HPV infection are beyond the scope of the present discussion and have been reviewed in detail elsewhere. 9 Briefly, however, for the present discussion it is important to understand that clinical diagnosis of infection (with the unaided eye) is convenient but extremely insensitive given that only large, primarily papillary lesions can be identified. Most HPV infections, especially those of the cervix, are flat and invisible to the unaided eye. 31 Furthermore, although many such cervical lesions can be visualized With the use of colposcopy, especially after the application of acetic acid, colposcopy has relatively low specificity and low sensitivity if used among women who are at high risk for contracting sexually transmitted diseases (STDs) and who have not been preselected on the basis of cytologic findings. 18 The use of microscopic examination of exfoliated cell samples (Papanicolaou smears) or tissue biopsy samples for detection of HPV (based on koilocytosis,32' ~3 abnormalities ofkeratinization, changes in the shape and size of the cytoplasm and the nucleus, and in the amount and distribution of the nuclear chromatin), is insensitive, nonspecific, and lacks inter- and intraobserver reproducibility.32 However, it is important to note that the microscopic morphologic changes of some CIN I and HPV are essentially identical. At present the gold standard for the diagnosis of HPV is detection of HPV DNA by hybridization technology; using either DNA and P~NA probes directed against specific types of HPV DNA with or without amplification of DNA. These techniques are specific and sensitive, especially if HPV DNA is amplified with the polymerase chain reaction before hybridization with HPV-specific probes. During the past decade investigators have described the prevalence of the various manifestations of HPV among different populations. Because it is STD, it is not surprising that the manifestations of productive HPV infections (the presence of clinically and colposcopically identified genital warts, microscopic evidence of cervical HPV infection including SIL of the cervix, and the detection of genital tract HPV DNA by hybridization) are most frequently detected among sexually active young women between 15 and 25 years old, frequently appearing shortly after beginning sexual activity. These manifestations of HPV as well as detection of cervical HPV DNA are only rarely detected in menopausal and postmenopausal women, perhaps reflecting immunity.34"38 Detection of cervical HPV DNA has been highly associated with cytologic and histologic changes consistent with CIN. Depending on the diagnostic method used, from 50% to more than 90% of women with CIN have been reported to be HPV DNA positive. 3z' 39Approximately 2.9% to 30% of younger women with normal cytologic findings are positive for high-risk genital HPV DNA, 9 with most of the HPV DNA detected being of unclassified types.
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We are only now beginning to gain insights into the natural history of HPV infection. Studies have been hindered by difficulties of diagnosis of active infection and the lack of an accurate serologic assay. What is known is that in most cases incident infection detected among young women beginning sexual activity, as well as infection detected among women coming to the STD clinic (documented by the presence of HPV DNA) resolves within 1 to 2 years (Koutsky and Kiviat, unpublished data). Not surprisingly, these data are similar to those reported in previous microscopic-based studies describing the natural history of CIN 1. As discussed below, from case-control studies it is clear that not all HPV infectious resolve and that a subset of infected women eventually develop malignancy. Howevm, it is becoming increasingly apparent that the natural history of most cervical HPV infection is remarkably similar to that described by most studies examining the natural history of CIN 1. These data strongly support the hypothesis that CIN 1 is simply the morphologic manifestation of a generally self-limited, sexually transmitted infectious process. In summary, HPV is an exceedingly c o m m o n STD, which in most patients appears to be self-limited and without serious consequences. The microscopic manifestation of infection and the natural history of the disease appear to be very similar to that of lesions currently classified as CIN 1.
HPV as the etiologic agent of many genital tract squamous cell cancers In addition to being a common STD, during the past decade several case-control and cohort studies have shown that specific types of HPV are the causal agent of most squamous epithelial cancers of the female and male genital u-acts. 4° The genital HPVs are classified as "high,." "intermediate," or "low" risk depending on the frequency with which they are detected in cancers. The most c o m m o n "high-risk" types include HPV types 16, 18, 45, and 56, whereas HPV types 31, 33, and 35, are referred to as "intermediate-risk" types. HPV 6, 11, 42, 43, and 44 (among immune competent individuals) are almost never found in association with malignant tumors and are therefore classified as "low-risk" types. 41 As mentioned previously, the tack of a serologic assay" has made it difficult to estimate the risk of malignancy conferred by infection with oncogenic types of HPV. However, several cohort studies describing the risk of development of CIN 2-3 in relation to HPV type have recently appeared. 26' 42In our studies of women attending an STD clinic who were cytologically negative at study entry, we found that the cumulative incidence of intraepithelial neoplasia grade 2-3 after 2 years of follow-up was 38% among women who had oncogenic HPV type 16 or 18 (as detected by Southern transfer hybridization) at some time during the study. After adjusting for HPV, factors that were independently associated with development o f CIN 2-3 included serologic evidence of Chlamydiae trachomatis and a positive culture for Neisseria gonorrhoeae. ~2 It has been hypothe-
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sized that the explanation for the association between infection with "high-risk" types of HPV and malignancy is related to the ability of the high, but not low risk, types of genital HPV to produce oncoproteins (designated E6 and ET) that bind normal tumor suppresser proteins P53 and pRB(42). It is also thought that infection with specific HPV types may be necessary but not sufficient to cause genital cancer and that malignant progression of HPVinfected lesions depends on the additional presence of cofactors such as infectious agents and chemical co-carcinogens and factors related to the host immune response.
Alternative interpretation of the relationship between CIN 1, CIN 2-3, and invasive cancer As discussed previously, it is now clear that HPV infections are central to both benign, self-limited, and malignant cervical pathologic lesions. Currently there is widespread acceptance of the hypothesis that most if not all CIN 3 lesions evolve slowly over time from a preexisting CIN 1 lesion. Data supporting this hypothesis include the observation that women diagnosed with invasive cervical cancer frequently have a previous history of CIN 1.4~45 However, an alternative explanation of such findings is that CIN 1 and CIN 3 are simply two distinct manifestations of HPV infection with distinct natural histories. Because both lesions are related to HPV, in the same way that CIN occurs more frequently in women with, compared with those without a history of vulvar warts, CIN 3 might be expected to occur more frequently among those women with, compared with those without, other manifestations of HPV infection. Another argument used to support the idea that CIN 3 evolves from CIN 1 is that CIN 1 is sometimes detected before CIN 3. Interestingly, however, in the cohort study described previously that examined the relationship between infection and highrisk types o f H P V DNA and the development of CIN 2-3,42 most women who developed CIN 2-3 never had evidence of a preceding CIN-1. Detection of high-risk types of HPV DNA was a better predictor of the development of CIN 2-3 than was detection of CIN 1. Similarly, Cuzick et al. 46 recently reported a high rate of biopsy proved CIN 2-3 among women with cytologically negative findings (who had no previous history of CIN 1) referred for biopsy on the basis of a positive test for detection of high-risk types of HPV cervical DNA. These investigators46 used cytology and testing for high or intermediate high-risk types of HPV to screen 2009 women who had no history of or treatment for an abnormal Papanicolaou smear within the previous 3 years. All women with either abnormal cytologic findings or a positive HPV test were then referred for colposcopy and biopsy. Of the 88 cases of biopsy confirmed CIN 2-3 detected, 33 had completely negative cytologic tests and were identified by HPV assays. Lastly, if CIN 2-3 does not arise from CIN 1, how does one explain the fact that the prevalence of CIN 1 appears to be highest in younger women, whereas CIS is more
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f r e q u e n t a m o n g slightly older women? It is possible that CIN 1 and CIN 2-3 lesions are established concurrently as two separate lesions that differ in their likelihood of detection. Such a situation m i g h t arise, for example, if these lesions differed in location or growth characteristics. Support for this idea comes f r o m studies that have d e m o n s t r a t e d that low-grade dysplasia generally occurs distal to CIS. 47 Low-grade lesions may therefore be m o r e accessible to sampling and colposcopic identification than are high-grade lesions. Supporting the hypothesis that CIN 2-3 lesions are established as such rather than e v o M n g over l o n g periods o f time f r o m o t h e r lesions is our finding of a tight t e m p o r a l relationship between detection of cervical HPV DNA 16/18 and the d e v e l o p m e n t of CIN 2-3 described previously, with most all CIN 2-3 d e t e c t e d within 6 m o n t h s after detection of cervical highrisk types o f HPV. In addition, laboratory-based studies of raft cultures of squamous e p i t h e l i u m ' i n f e c t e d with HPV 16/18 show m o r p h o l o g i c changes that resemble those seen with CIN 2-3. It is possible that CIN 2-3 lesions vary considerably in their m a l i g n a n t potential even t h o u g h they a p p e a r to be morphologically h o m o g e n e o u s . Some lesions classified as consistent with CIN 2-3 simply represent infection of metaplastic e p i t h e l i u m with specific types of HPV and spontaneously resolve, whereas others may persist and evolve into the true precursors ofinvasive cancers. It is possible therefore that many of the lesions we d e t e c t e d a m o n g w o m e n c o m i n g to an STD clinic (because of symptoms or exposure to o t h e r STDs) would have disappeared before theywere ever d e t e c t e d cytologically had the w o m e n n o t b e e n closely m o n i t o r e d for the presence o f a b n o r m a l cytologic findings. These are issues that n e e d further investigation, because d e t e r m i n i n g w h e t h e r CIN 1 lesions are simply markers of exposure to HPV (the etiologic a g e n t of cervical agent) or truly are cervical cancer precursor lesions will allow us to devise appropriate clinical m a n a g e m e n t of these lesions. In summary, a l t h o u g h we have m a d e impressive progress in cervical cancer control in the past 40 years, o u r c u r r e n t a p p r o a c h does n o t appear to incorporate new i n f o r m a t i o n on the role of HPV as a c o m m o n STD as well as the causative agent of most cancers. It is likely that by doing so we can design m o r e efficient and cost-effective strategies for control of cervical cancer.
REFERENCES
1. Harlan LC, Bernstein AB, Kessler LG. Cervical cancer screening: who is not screened and why? AmJ Public Health 1991;81:885-90. 2. Bethesda System. The 1988 Bethesda system for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262: 931-4. 3. Blomfield PI, Buxton J, Dunn J, Luesley DM. Pregnancy outcome after large loop excision of the cervical transformation zone. A m J Obstet Gynecol 1993;169:620-5. 4. NaxA, Bothorel R RenaudieJ, Piver P, Chameau OJ, Eyraud JR et al. Diagnosis and treatment of cervical dysplasia: report of 42 cases. Rev Fr Gynecol Obstet 1990;85:587-93. 5. Herzgog T, Williams S, Adler LM, Rader JS, Kubiniec RT,
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Camel HM, et al. Potential of cervical electrosurgical excision procedure for diagnosis and treatment of cervical intraepithelial neoplasia. Gynecol Oncol 1995;57:286-93. 6. MerguiJL, Tauscher P, Bergeron C, Pambou O, Salat Baroux J. Electro-conization with the diathermic loop: indications and results. Contracept Fertil Sex 1994;22:53-9. 7. Loizzi P, Carriero C, Di Gesu A, Resta L, Nappi R. Rational use of cryosurgery" and cold knife conization for treatment of cervical intraepithelial neoplasia. EurJ Gynaecol Oncol 1992;13:507-13. 8. Hillard PA, Biro FM, Wildey L. Complications of cervical cryotherapy in adolescents. J Reprod Med 1991;36:711-6. 9. Kiviat NB, Koutsky LA, Paavonen JA, Galloway D, Critchlow C, Beckmann A, et al. Prevalence of genital papillomavirus infection among women attending a college student health clinic or a sexually transmitted disease clinic. J Infect Dis 1989;159:293-302. 10. Herbst AL. The Bethesda System for cervical/vaginal cytologic diagnoses. Clin Obstet Gynecol 1992;35:22-7. 11. Schauenstein W. Histologische Untersuchungen uber atypisches Plattenepithel an der Portio und an der Inneflache der Cervix uteri. Arch Gynak 1908;85:576. 12. Schottlaender J, Dermauner F. Zur Kenntnis des Uteruskarzinoms. Berlin: S Kargei; 1912:912. 13. Broders AC. Carcinoma in situ contrasted with benign penetrating epithelium. JAMA 1932;99:1670-4. 14. Jones HW, Butler RE. Re-examination of biopsies taken prior to the development of invasive carcinoma of the cervLx. In: Proceedings of the Third National Cancer Conference. Philadelphia: JB Lippincott, 1956:678. 15. Lange R Clinical and histological studies on cervical carcinoma. Acta Pathol Microbiol Scand 1960;50(suppl 143): 13-6. 16. Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. IntJ Gynecol Patho11993;12:18692. 17. Wright TC, Kurman RJ, ForenczyA. Precancerous lesions of the cervix. In: Kurman RJ, ed. Blaustein's pathology of the female genital tract, 4th ed. New York: Springer-Verlag, 1995;7:229-77. 18. Paavonen J, Stevens CE, Wolner-Hanssen P, et al. Colposcopic manifestations of cervical and vaginal infections. Obstet Gynecol Surv 1988;43:373-81. 19. Buckley CH, Butler EB, Fox H. Cervical intraepithelial neoplasia. J Clin Pathol 1982;35:1-13. 20. Reagan JW, Seidemann IL, Saracusa Y The cellular morphology of carcinoma in situ and dysplasia or atypical hyperplasia of the uterine cervix. Cancer 1953;6:224-35. 21. Nasiell K, Nasiell M, Vaclavinkova V. Behavior of moderate cervical dysplasia during long-term follow-up. Obstet Gyneeol 1983;61:609-14. 22. Nasiell K, Roger V, Nasiell M. Behavior of mild cervical dysplasia during long-term follow-up. Obstet Gynecol 1986; 67:665-9. 23. Baron BA, Richart RM. A statistical mode of the natural history of cervical carcinoma based on a prospective study of 557 cases.J Natl Cancer Inst 1968;41:1343-53. 24. Barron BA, Richart RM. A statistical model of the natural history of cervical carcinoma. II. Estimates of the transition time from dysplasia to carcinoma in situ. J Natl Cancer Inst 1970;45:1025-36. 25. Richart RM, Barron BA. A follow-up study of patients with cervical dysplasia. AmJ Obstet Gyneeol 1969;105:386-93. 26. Campion MJ, Cuzick J, McCance DJ, Singer A. Progressive potential of mild cervical atypia: prospective cytological, colposcopic, a n d virological study. Lancet 1986;2:23740. 27. Okagaki T, Lerch V, Younge PA, McKay DG, Kervokian AY. Diagnosis of anaplasia and carcinoma in situ by differential cell counts. Acta Cytol 1962;6:343-7. 28. Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122-63. 29. Kiviat NB, Koutsky LA. Human papillomavirus. In: Murray PR, et al., eds. Manual of clinical microbiology, 6th ed. Washington, DC: ASM Press, 1995:1082-90.
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30. McDougallJK, Beckmann AA, Kiviat NB. Methods for diagnosing papillomavirus infection. In: Papillomaviruses. CIBA Found Symposium 120. Chichester, England: John Wiley, 1986:86-103. 31. Paavonen J, Koutsky LA, Kiviat N. Cervical neoplasia and other STD-related genital and anal neoplasias. In: Holmes KK, Mardh R Sparling PF, Wiesner PJ, Cates W Jr, Lemon SM, Stamm ~rE, editors. Sexually transmitted diseases, 2nd ed. New York: McGraw-Hill, 1990:561-92. 32. KMat NB, Koutsky LA, Critchlow CW, et al. Prevalence and cytologic manifestations of human papillomavirus (HPV) types 6, 11, 16, 18, 33, 35, 42, 43, 44, 45, 51, 52, and 56 among 500 consecutive women. I n t J Gynecol Pathol 1992;11:197203. 33. Schneider A, Koutsky L. Natural history and epidemiological features of genital HPV infection. In: Munoz N, Bosch FX, Shah KV, Meheus A, editors. The epidemiology of cervical cancer and human papillomavirus. IARC Scientific Publications No. 19. Lyon, France: International Agency for Research on Cancer, 1992:25-52. 34. Critchlow CW, Koutsky LA. Epidemiology of human papillomavirus infection. In: Mindel A, editor. Genitalwarts: human papillomavirus infection. London: Edward Arnold, 1995. 35. CzegledyJ, Rogo KO, Evander M, Wadel!G. High-risk human papillomavirus types in cytologically normal cervical scrapes from Kenya. Med Microbiol Immuno11992;180:321-6. 36. Kjaer SK, Lynge E. Incidence, prevalence and time trends of genital HPV infection determined by clinical examination and cytology. In: Munoz N, Bosch FX, Jensen OM, editors. Human papillomavirus and cervical cancer. IARC Scientific Publications No. 94. Lyon, France: International Agency for Research on Cancer, 1989:113-24. 37. Melkert PWJ, Hopman E, van den Brule A, et al. Prevalence of HPV in cytomorphologically normal cervical smears, as determined by the polymerase chain reaction, is age-dependent. I n t J Cancer 1993;53:919-23.
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38. Pao CC, Lin C-Y, Maa J-S, Lai C-H, Wu S-Y, Soong Y-K. Detection of human papillomaviruses in cervicovaginal cells using polymerase chain reaction.J Infect Dis 1990;161:113-5. 39. Schiffman MH. Commentary: recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. J Nat Cancer Inst 1992;84:394-8. 40. Munoz N, Bosch FX, de Sanjose S, et al. The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. IntJ Cancer 1992;52:743-9. 41. Lorincz AT, Reid R,Jenson AB, Greenberg MD, Lancaster W, Kurman RJ. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 1992;79:328-37. 42. Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Englj Med 1992;327: 1272-8. 43. Brinton LA. Epidemiology of cervical cancer--overview. Epidemiology of human papillomavirus and cervical cancer. IARC Scientific Publication 119. Lyon, France: International Agency for Research on Cancer 1992;3-23. 44. Burghardt E, Ostor AG. Site and origin ofsquamous cervical cancer: a histomorphologic study. Obstet Gynecol 1983;62: 117-27. 45. Stern E, Neely PM. Carcinoma and dysplasia of the cervix: a comparison of rates for new and returning populations. Acta Cytol 1963;7:357-61. 46. CuzickJ, Szarewski A, Terry G, et al. Human papillomavirus testing in primary cervical screening. Lancet 1995;345: 1533-6. 47. Saito K, Saito A, Fu YS, Smotkin D, GuptaJ, Shah IL Topographic study of cervical condyloma and intraepithelial neoplasia. Cancer 1987;59:2064-70.
Seattle, Washington Current cervical cancer control strategies and specifically, the screening and treatment policies that have been used during the past 30 years, are based on an understanding of the natural history of cervical neopiasia that does not take into account the important role of human papiltomavirus in cervical cancer pathogenesis. This survey presents a review of new data on the causes of cervical cancer and the role of human papillomavirus and recommends the integration of these data. Incorporation of new information on the role of human papillomavirus as the causative agent of most cervical cancers will allow the design of more efficient and more cost-effective strategies for cervical cancer control. (Am J Qbstet Gynecol 1996;175:1099-104.)
During the past 50 years mortality rates of cervical cancer have dramatically decreased. ~Although it is likely that some decline in mortality- rates of cervical cancer occurred before the establishment of public health programs focused on cervical cancer control, it has been well documented that the greatest decreases in mortality rates of cervical cancer occurred at specific sites subsequent to implementation of cervical cancer screening. ~The development of current control strategies for cervical cancer and specifically, screening and treatment policies that have been used during the past 30 years, are based on a view of the natural history of cervical neoplasia that predates the discovery of the importance of h u m a n papillomavirus (HPV) in cervical cancer pathogenesis. Although our current approach to cervical cancer control has been successful in lowering mortality rates of cervical cancer, it is widely acknowledged to be inefficient and costly. Recent studies discussed herein, which demonstrate the central role of HPV in both benign and malignant cervical disease, have raised questions about the validity of our currently accepted beliefs about the natural history of lesions classified as "dysplasia" or "cervical intraepithelial neoplasia." If we can incorporate what has been learned about HPV and its relationship to cervical disease into cervical cancer control policies, we can increase the cost-effectiveness of such programs. Current cervical c a n c e r control strategies
Cervical cancer control programs are based on the belief that invasive cervical cancer arises from more treatable localized lesions, termed "carcinoma in situ" or "cervical intraepithelial neoplasia grade 3" (CIS/CIN 3). These lesions, which are thought to be the immediate
From the Departmenl of Patholog)~, University of Washington. Reprint requests: Nancy Kiviat, MD, Department of Pathology, University of Washington, HPV Research Group, 6 Nickerson St., Suite 310, Seattle, WA 98109. Copyrigkt © 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/0/76602
precursors of invasive cervical cancel, can be easily removed to prevent the development of invasive disease. Therefore the primary aim of cytologic screening has been identification of women with CIS/CIN 3 (term consistent with "high-grade squamous intraepithelial lesions" (SIL) or CIS when identified on Papanicolaou smears). In addition, during the past 30 years, it has been widely accepted that CIN 1, CIN 2, and CIN 3 represent progressive successive stages in the development of invasive cervical cancer (see "Historical and Scientific Basis" section below). Therefore cytologic screening has also focused on identification of women with CIN 1 and CIN 2. Another cervical epithelial lesion that many feel may have malignant potential is termed "squamous atypia" (when identified histologically) or "atypical squamous cells of uncertain significance" (ASCUS) if detected on Papanicolaou smears, z Because this lesion is characterized by less marked cellular abnormalities than are CIN lesions, it has been suggested that it represents a still earlier stage in cervical cancer pathogenesis. Currently all women who have cytologic evidence of highgrade SIL or its equivalent, the majority of women with low-grade SIL (the cytologic equivalent of CIN 1), and those with repeated ASCUS or atypia are referred for colposcopy and biopsy. Women in whom a biopsy specimen confirms the presence of CIN 2-3 and many of those with biopsy" confirmed CIN 1 then undergo ablation of transformation zone epithelium. The rationale for follow-up and treatment of women with repeated atypia and CIN 1 is the belief that "squamous atypia," CIN 1, CIN 2, and CIN 3/CIS represent successive progressive stages in the pathogenesis of cervical cancer. Shortcomings of current cervical c a n c e r control strategies
Screening for and treatment of the lesions described previously have clearly led to a decrease in mortality rates of cervical cancer. However, this strategy is not without problems. It is well established that ablation of the trans1099
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formation zone is not completely without morbidity,e~8 Furthermore, identification a n d treatment of ASCUS, CIN 1, and CIN 2, in addition to CIN 3 and CIS, are costly. For example, the prevalence of CIN 1 has been reported to be as high as 13% among young sexually active women, 9 making this an extremely common lesion. Costs for colposcopy and biopsy range from $150 to $750, whereas ablative therapy ranges from $200 to over $2000 depending on the modality used (survey of 18 centers in the United States by A. Herbst? ° Assuming (conservatively) that only 1% of women between 15 and 49 years old have low-grade SIL, that all are referred for colposcopy and biopsy at a cost of $200, and that 50% are treated, the annual cost of such an approach would exceed 200 million dollars. Furthermore, atypia or ASCUS is found in 10% to 30% of Papanicolaou smears depending on the population examined. If one assumes that only 15 % of women with ASCUS require repeat cytologic studies at a cost of $30 and that 30% of these women will subsequently undergo colposcopy and biopsy, this would result in at least an additional $300 million being spent annually. The figures suggest that such an approach may not be justified. To determine the validity of this approach, we need to examine more closely the historical perspective and scientific basis for current policies.
Historical and scientific basis for current management of strategies for women with abnormal cytologic and histologic findings Modern studies of the pathogenesis of cervical cancer date from the turn of the century when a few investigators undertook systematic microscopic examination of the uteri of women with cervical cancer] ~-13These early investigators noted that the architecture of the cervical epithelium appeared intact in areas adjacent to invasive tumors. The normal epithelial cells in such areas, however, were frequently replaced by a population of cells whose morphologic features resembled the cells seen within the invasive tumor mass. It was hypothesized that such lesions were precursors of invasive cancers and therefore such lesions were termed "carcinoma in situ." The logical extension of this hypothesis was that women in whom such lesions were present but who did not have invasive cancer would develop invasive cancer if such tissue was not removed. As the idea that untreated CIS had a high likelihood of progression to invasive cancer quickly gained popularity, it soon became unethical to carry out studies to actually test this hypothesis. Therefore todaywe know little about the true risk of development of invasive cancer associated with untreated CIS. What little data exist comes primarily from a small series of women with CIS who inadvertently were not treated. In addition, in several series undertaken before ablative treatment became the accepted standard of care, women repeatedly underwent biopsies rather than given definitive treat-
October 1996 AmJ Obstet Gynecol
ment.14. 15 Review of available data suggests that, if left untreated, CIS would regress in approximately 10% to 30% of women and that from 12% to 70% would develop invasive disease within the span of a normal lifetime? ~-18 After acceptance of the concept of CIS by the medical community, pathologists began to document the existence of other cervical abnormalities, now referred to as CIN and squamous atypia. These lesions are made up of a population of more differentiated cells than those seen in CIS. On the basis of their less striking morphologic changes and the fact that they appeared to be present more frequently in women without cervical cancer, it was hypothesized that they represented earlier stages in cervical cancer pathogenesis than did CIS. 19' 20 How strong is the data supporting the now-popular view that these lesions (CIN 1, CIN 2, and CIN 3) represent a morphologic and biologic continuum of progressive consecutive stages in the development of invasive cancer? Numerous studies have described the risk of progression of CIN 1 and CIN 2 to CIS. Differences in study entry criteria, length of follow-up, follow-up procedures (e.g., repeated biopsy vs follow-up by Papanicolaou smear alone), and statistical methodology make comparisons of these studies difficult. However, most studies suggest that from 10% to 15% of women with CIN 1 who are followed without biopsy will subsequently develop CIN 2-3. At least 60% will have smears that regress to normal, and approximately 30% will have persistence of CIN 1.1e~I8'21, 22 The rate of regression appears even higher when considering those women who have had only a single Papanicolaou smear showing low-grade SIL on study entry. However, in contrast to the overwhelming majority of natural history studies, the results from one of the first large studies of this type reported that more than 50% of women with low-grade SIL developed CIN 3 within 5 years. 2~-25Furthermore, almost no regression occurred in this later study. On the basis of this study Barron and Richart proposed the "cervical intraepithelial neoplasia" classification system. This classification system has served as the basis for the diagnosis and clinical management of cervical disease in the past 20 years. Inherent in this classification system is the belief that the various morphologic changes observed on Papanicolaou smears and biopsy represented successive (increasingly abnormal) stages in the pathogenesis of cervical cancer. To emphasize that these lesions represent a continuum in development of malignancy, they were collectively termed "cervical intraepithelial neoplasia" grades 1, 2, and 3. 25 Most other natural history studies did not support this hypothesis, but had in fact demonstrated that low-grade SIL was generally a benign lesion. Despite this fact, the idea that untreated CIN 1 had a high probability of becoming invasive cancer has had widespread acceptance and served as the rationale for aggressive management of these lesions. The markedly higher rate of progression
Volume 175, Number 4, Part 9 AmJ Obstet Gynecol
and lack of regression seen in the Richart and several other more recent studies, 26as compared with most other studies, is partly related to study entry criteria. Richart and Baron required that study participants have multiple previous smears showing CIN 1. Because most regression of CIN 1 normally occurs during the first year or two after an initial cytologic detection of CIN 1, such entry c r i t e r i a inadvertently selected for those women who were most ]ikely to have lesions that would not regress. Therefore although the results of the Richart and Barron study may provide insights into the natural history of CIN 1 lesions that have persisted for at least a 1-year period, this study tells us little about the natural history of most CIN 1 lesions. Other studies that did not have similar entry criteria provide more valuable information about the appropriate clinical management of women with incident CIN or atypia. Furthermore, some of the women classified to have CIN 1 according to the Okagaki cytologic classification s y s t e m 27 used in the Richart and Barron study would have been assigned a diagnosis of CIN 3 by the World Health Organization system used in most other studies. In summary, most available data suggest that CIN 1 lesions and atypias do not generally progress.
HPV infection and cervical pathology HPV infection of the genital tract has now been convincingly demonstrated to be the most common sexually transmitted viral infection in the United States. 2s Genital warts have long been known to occur on the vulva, vagina, cervix, penis, and anus29; however, only recently has it become clear that a n u m b e r of different sexually transmitted v i r u s e s a r e responsible for all of these lesions. Furthermore, it is now apparent that the flat lesions seen with the aid of a colposcope after application of acetic acid (which were traditionally classified by colposcopists as consistent with CIN) are related to the typical genital warts seen on the vulva and penis. All these lesions a r e manifestations of ttPV infection. Lastly, we have learned that the microscopic manifestations of HPV infection a r e among those morphologic changes normally classified by pathologists as consistent with CIN. Traditional techniques for culturing viruses cannot be used for identification of HPV infection as replication of HPV with complete capsid formation occurs only in terminally differentiated squamous cells. Therefore other techniques for diagnosis have been used including clinical, colposcopic, and microscopic examination. More recently, HPV DNA has been detected by hybridization with or without prior amplification of specific types of HPV DNA. s° The absence of a culture system has made development of a serologic assay extremely difficult; as a result, we have no estimate of the lifetime risk of exposure to these viruses. Only with the recent development and application of newer assays have we gained a true appreciation of the high prevalence of infection with the sexually
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transmitted types of this virus. ~s The advantages and limitations of specific assays for detection of HPV infection are beyond the scope of the present discussion and have been reviewed in detail elsewhere. 9 Briefly, however, for the present discussion it is important to understand that clinical diagnosis of infection (with the unaided eye) is convenient but extremely insensitive given that only large, primarily papillary lesions can be identified. Most HPV infections, especially those of the cervix, are flat and invisible to the unaided eye. 31 Furthermore, although many such cervical lesions can be visualized With the use of colposcopy, especially after the application of acetic acid, colposcopy has relatively low specificity and low sensitivity if used among women who are at high risk for contracting sexually transmitted diseases (STDs) and who have not been preselected on the basis of cytologic findings. 18 The use of microscopic examination of exfoliated cell samples (Papanicolaou smears) or tissue biopsy samples for detection of HPV (based on koilocytosis,32' ~3 abnormalities ofkeratinization, changes in the shape and size of the cytoplasm and the nucleus, and in the amount and distribution of the nuclear chromatin), is insensitive, nonspecific, and lacks inter- and intraobserver reproducibility.32 However, it is important to note that the microscopic morphologic changes of some CIN I and HPV are essentially identical. At present the gold standard for the diagnosis of HPV is detection of HPV DNA by hybridization technology; using either DNA and P~NA probes directed against specific types of HPV DNA with or without amplification of DNA. These techniques are specific and sensitive, especially if HPV DNA is amplified with the polymerase chain reaction before hybridization with HPV-specific probes. During the past decade investigators have described the prevalence of the various manifestations of HPV among different populations. Because it is STD, it is not surprising that the manifestations of productive HPV infections (the presence of clinically and colposcopically identified genital warts, microscopic evidence of cervical HPV infection including SIL of the cervix, and the detection of genital tract HPV DNA by hybridization) are most frequently detected among sexually active young women between 15 and 25 years old, frequently appearing shortly after beginning sexual activity. These manifestations of HPV as well as detection of cervical HPV DNA are only rarely detected in menopausal and postmenopausal women, perhaps reflecting immunity.34"38 Detection of cervical HPV DNA has been highly associated with cytologic and histologic changes consistent with CIN. Depending on the diagnostic method used, from 50% to more than 90% of women with CIN have been reported to be HPV DNA positive. 3z' 39Approximately 2.9% to 30% of younger women with normal cytologic findings are positive for high-risk genital HPV DNA, 9 with most of the HPV DNA detected being of unclassified types.
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We are only now beginning to gain insights into the natural history of HPV infection. Studies have been hindered by difficulties of diagnosis of active infection and the lack of an accurate serologic assay. What is known is that in most cases incident infection detected among young women beginning sexual activity, as well as infection detected among women coming to the STD clinic (documented by the presence of HPV DNA) resolves within 1 to 2 years (Koutsky and Kiviat, unpublished data). Not surprisingly, these data are similar to those reported in previous microscopic-based studies describing the natural history of CIN 1. As discussed below, from case-control studies it is clear that not all HPV infectious resolve and that a subset of infected women eventually develop malignancy. Howevm, it is becoming increasingly apparent that the natural history of most cervical HPV infection is remarkably similar to that described by most studies examining the natural history of CIN 1. These data strongly support the hypothesis that CIN 1 is simply the morphologic manifestation of a generally self-limited, sexually transmitted infectious process. In summary, HPV is an exceedingly c o m m o n STD, which in most patients appears to be self-limited and without serious consequences. The microscopic manifestation of infection and the natural history of the disease appear to be very similar to that of lesions currently classified as CIN 1.
HPV as the etiologic agent of many genital tract squamous cell cancers In addition to being a common STD, during the past decade several case-control and cohort studies have shown that specific types of HPV are the causal agent of most squamous epithelial cancers of the female and male genital u-acts. 4° The genital HPVs are classified as "high,." "intermediate," or "low" risk depending on the frequency with which they are detected in cancers. The most c o m m o n "high-risk" types include HPV types 16, 18, 45, and 56, whereas HPV types 31, 33, and 35, are referred to as "intermediate-risk" types. HPV 6, 11, 42, 43, and 44 (among immune competent individuals) are almost never found in association with malignant tumors and are therefore classified as "low-risk" types. 41 As mentioned previously, the tack of a serologic assay" has made it difficult to estimate the risk of malignancy conferred by infection with oncogenic types of HPV. However, several cohort studies describing the risk of development of CIN 2-3 in relation to HPV type have recently appeared. 26' 42In our studies of women attending an STD clinic who were cytologically negative at study entry, we found that the cumulative incidence of intraepithelial neoplasia grade 2-3 after 2 years of follow-up was 38% among women who had oncogenic HPV type 16 or 18 (as detected by Southern transfer hybridization) at some time during the study. After adjusting for HPV, factors that were independently associated with development o f CIN 2-3 included serologic evidence of Chlamydiae trachomatis and a positive culture for Neisseria gonorrhoeae. ~2 It has been hypothe-
October 1996 AmJ Obstet Gynecol
sized that the explanation for the association between infection with "high-risk" types of HPV and malignancy is related to the ability of the high, but not low risk, types of genital HPV to produce oncoproteins (designated E6 and ET) that bind normal tumor suppresser proteins P53 and pRB(42). It is also thought that infection with specific HPV types may be necessary but not sufficient to cause genital cancer and that malignant progression of HPVinfected lesions depends on the additional presence of cofactors such as infectious agents and chemical co-carcinogens and factors related to the host immune response.
Alternative interpretation of the relationship between CIN 1, CIN 2-3, and invasive cancer As discussed previously, it is now clear that HPV infections are central to both benign, self-limited, and malignant cervical pathologic lesions. Currently there is widespread acceptance of the hypothesis that most if not all CIN 3 lesions evolve slowly over time from a preexisting CIN 1 lesion. Data supporting this hypothesis include the observation that women diagnosed with invasive cervical cancer frequently have a previous history of CIN 1.4~45 However, an alternative explanation of such findings is that CIN 1 and CIN 3 are simply two distinct manifestations of HPV infection with distinct natural histories. Because both lesions are related to HPV, in the same way that CIN occurs more frequently in women with, compared with those without a history of vulvar warts, CIN 3 might be expected to occur more frequently among those women with, compared with those without, other manifestations of HPV infection. Another argument used to support the idea that CIN 3 evolves from CIN 1 is that CIN 1 is sometimes detected before CIN 3. Interestingly, however, in the cohort study described previously that examined the relationship between infection and highrisk types o f H P V DNA and the development of CIN 2-3,42 most women who developed CIN 2-3 never had evidence of a preceding CIN-1. Detection of high-risk types of HPV DNA was a better predictor of the development of CIN 2-3 than was detection of CIN 1. Similarly, Cuzick et al. 46 recently reported a high rate of biopsy proved CIN 2-3 among women with cytologically negative findings (who had no previous history of CIN 1) referred for biopsy on the basis of a positive test for detection of high-risk types of HPV cervical DNA. These investigators46 used cytology and testing for high or intermediate high-risk types of HPV to screen 2009 women who had no history of or treatment for an abnormal Papanicolaou smear within the previous 3 years. All women with either abnormal cytologic findings or a positive HPV test were then referred for colposcopy and biopsy. Of the 88 cases of biopsy confirmed CIN 2-3 detected, 33 had completely negative cytologic tests and were identified by HPV assays. Lastly, if CIN 2-3 does not arise from CIN 1, how does one explain the fact that the prevalence of CIN 1 appears to be highest in younger women, whereas CIS is more
Volume 175, Number 4, Part 2 _~nJ Obstet Gynecot
f r e q u e n t a m o n g slightly older women? It is possible that CIN 1 and CIN 2-3 lesions are established concurrently as two separate lesions that differ in their likelihood of detection. Such a situation m i g h t arise, for example, if these lesions differed in location or growth characteristics. Support for this idea comes f r o m studies that have d e m o n s t r a t e d that low-grade dysplasia generally occurs distal to CIS. 47 Low-grade lesions may therefore be m o r e accessible to sampling and colposcopic identification than are high-grade lesions. Supporting the hypothesis that CIN 2-3 lesions are established as such rather than e v o M n g over l o n g periods o f time f r o m o t h e r lesions is our finding of a tight t e m p o r a l relationship between detection of cervical HPV DNA 16/18 and the d e v e l o p m e n t of CIN 2-3 described previously, with most all CIN 2-3 d e t e c t e d within 6 m o n t h s after detection of cervical highrisk types o f HPV. In addition, laboratory-based studies of raft cultures of squamous e p i t h e l i u m ' i n f e c t e d with HPV 16/18 show m o r p h o l o g i c changes that resemble those seen with CIN 2-3. It is possible that CIN 2-3 lesions vary considerably in their m a l i g n a n t potential even t h o u g h they a p p e a r to be morphologically h o m o g e n e o u s . Some lesions classified as consistent with CIN 2-3 simply represent infection of metaplastic e p i t h e l i u m with specific types of HPV and spontaneously resolve, whereas others may persist and evolve into the true precursors ofinvasive cancers. It is possible therefore that many of the lesions we d e t e c t e d a m o n g w o m e n c o m i n g to an STD clinic (because of symptoms or exposure to o t h e r STDs) would have disappeared before theywere ever d e t e c t e d cytologically had the w o m e n n o t b e e n closely m o n i t o r e d for the presence o f a b n o r m a l cytologic findings. These are issues that n e e d further investigation, because d e t e r m i n i n g w h e t h e r CIN 1 lesions are simply markers of exposure to HPV (the etiologic a g e n t of cervical agent) or truly are cervical cancer precursor lesions will allow us to devise appropriate clinical m a n a g e m e n t of these lesions. In summary, a l t h o u g h we have m a d e impressive progress in cervical cancer control in the past 40 years, o u r c u r r e n t a p p r o a c h does n o t appear to incorporate new i n f o r m a t i o n on the role of HPV as a c o m m o n STD as well as the causative agent of most cancers. It is likely that by doing so we can design m o r e efficient and cost-effective strategies for control of cervical cancer.
REFERENCES
1. Harlan LC, Bernstein AB, Kessler LG. Cervical cancer screening: who is not screened and why? AmJ Public Health 1991;81:885-90. 2. Bethesda System. The 1988 Bethesda system for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262: 931-4. 3. Blomfield PI, Buxton J, Dunn J, Luesley DM. Pregnancy outcome after large loop excision of the cervical transformation zone. A m J Obstet Gynecol 1993;169:620-5. 4. NaxA, Bothorel R RenaudieJ, Piver P, Chameau OJ, Eyraud JR et al. Diagnosis and treatment of cervical dysplasia: report of 42 cases. Rev Fr Gynecol Obstet 1990;85:587-93. 5. Herzgog T, Williams S, Adler LM, Rader JS, Kubiniec RT,
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Camel HM, et al. Potential of cervical electrosurgical excision procedure for diagnosis and treatment of cervical intraepithelial neoplasia. Gynecol Oncol 1995;57:286-93. 6. MerguiJL, Tauscher P, Bergeron C, Pambou O, Salat Baroux J. Electro-conization with the diathermic loop: indications and results. Contracept Fertil Sex 1994;22:53-9. 7. Loizzi P, Carriero C, Di Gesu A, Resta L, Nappi R. Rational use of cryosurgery" and cold knife conization for treatment of cervical intraepithelial neoplasia. EurJ Gynaecol Oncol 1992;13:507-13. 8. Hillard PA, Biro FM, Wildey L. Complications of cervical cryotherapy in adolescents. J Reprod Med 1991;36:711-6. 9. Kiviat NB, Koutsky LA, Paavonen JA, Galloway D, Critchlow C, Beckmann A, et al. Prevalence of genital papillomavirus infection among women attending a college student health clinic or a sexually transmitted disease clinic. J Infect Dis 1989;159:293-302. 10. Herbst AL. The Bethesda System for cervical/vaginal cytologic diagnoses. Clin Obstet Gynecol 1992;35:22-7. 11. Schauenstein W. Histologische Untersuchungen uber atypisches Plattenepithel an der Portio und an der Inneflache der Cervix uteri. Arch Gynak 1908;85:576. 12. Schottlaender J, Dermauner F. Zur Kenntnis des Uteruskarzinoms. Berlin: S Kargei; 1912:912. 13. Broders AC. Carcinoma in situ contrasted with benign penetrating epithelium. JAMA 1932;99:1670-4. 14. Jones HW, Butler RE. Re-examination of biopsies taken prior to the development of invasive carcinoma of the cervLx. In: Proceedings of the Third National Cancer Conference. Philadelphia: JB Lippincott, 1956:678. 15. Lange R Clinical and histological studies on cervical carcinoma. Acta Pathol Microbiol Scand 1960;50(suppl 143): 13-6. 16. Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. IntJ Gynecol Patho11993;12:18692. 17. Wright TC, Kurman RJ, ForenczyA. Precancerous lesions of the cervix. In: Kurman RJ, ed. Blaustein's pathology of the female genital tract, 4th ed. New York: Springer-Verlag, 1995;7:229-77. 18. Paavonen J, Stevens CE, Wolner-Hanssen P, et al. Colposcopic manifestations of cervical and vaginal infections. Obstet Gynecol Surv 1988;43:373-81. 19. Buckley CH, Butler EB, Fox H. Cervical intraepithelial neoplasia. J Clin Pathol 1982;35:1-13. 20. Reagan JW, Seidemann IL, Saracusa Y The cellular morphology of carcinoma in situ and dysplasia or atypical hyperplasia of the uterine cervix. Cancer 1953;6:224-35. 21. Nasiell K, Nasiell M, Vaclavinkova V. Behavior of moderate cervical dysplasia during long-term follow-up. Obstet Gyneeol 1983;61:609-14. 22. Nasiell K, Roger V, Nasiell M. Behavior of mild cervical dysplasia during long-term follow-up. Obstet Gynecol 1986; 67:665-9. 23. Baron BA, Richart RM. A statistical mode of the natural history of cervical carcinoma based on a prospective study of 557 cases.J Natl Cancer Inst 1968;41:1343-53. 24. Barron BA, Richart RM. A statistical model of the natural history of cervical carcinoma. II. Estimates of the transition time from dysplasia to carcinoma in situ. J Natl Cancer Inst 1970;45:1025-36. 25. Richart RM, Barron BA. A follow-up study of patients with cervical dysplasia. AmJ Obstet Gyneeol 1969;105:386-93. 26. Campion MJ, Cuzick J, McCance DJ, Singer A. Progressive potential of mild cervical atypia: prospective cytological, colposcopic, a n d virological study. Lancet 1986;2:23740. 27. Okagaki T, Lerch V, Younge PA, McKay DG, Kervokian AY. Diagnosis of anaplasia and carcinoma in situ by differential cell counts. Acta Cytol 1962;6:343-7. 28. Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122-63. 29. Kiviat NB, Koutsky LA. Human papillomavirus. In: Murray PR, et al., eds. Manual of clinical microbiology, 6th ed. Washington, DC: ASM Press, 1995:1082-90.
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30. McDougallJK, Beckmann AA, Kiviat NB. Methods for diagnosing papillomavirus infection. In: Papillomaviruses. CIBA Found Symposium 120. Chichester, England: John Wiley, 1986:86-103. 31. Paavonen J, Koutsky LA, Kiviat N. Cervical neoplasia and other STD-related genital and anal neoplasias. In: Holmes KK, Mardh R Sparling PF, Wiesner PJ, Cates W Jr, Lemon SM, Stamm ~rE, editors. Sexually transmitted diseases, 2nd ed. New York: McGraw-Hill, 1990:561-92. 32. KMat NB, Koutsky LA, Critchlow CW, et al. Prevalence and cytologic manifestations of human papillomavirus (HPV) types 6, 11, 16, 18, 33, 35, 42, 43, 44, 45, 51, 52, and 56 among 500 consecutive women. I n t J Gynecol Pathol 1992;11:197203. 33. Schneider A, Koutsky L. Natural history and epidemiological features of genital HPV infection. In: Munoz N, Bosch FX, Shah KV, Meheus A, editors. The epidemiology of cervical cancer and human papillomavirus. IARC Scientific Publications No. 19. Lyon, France: International Agency for Research on Cancer, 1992:25-52. 34. Critchlow CW, Koutsky LA. Epidemiology of human papillomavirus infection. In: Mindel A, editor. Genitalwarts: human papillomavirus infection. London: Edward Arnold, 1995. 35. CzegledyJ, Rogo KO, Evander M, Wadel!G. High-risk human papillomavirus types in cytologically normal cervical scrapes from Kenya. Med Microbiol Immuno11992;180:321-6. 36. Kjaer SK, Lynge E. Incidence, prevalence and time trends of genital HPV infection determined by clinical examination and cytology. In: Munoz N, Bosch FX, Jensen OM, editors. Human papillomavirus and cervical cancer. IARC Scientific Publications No. 94. Lyon, France: International Agency for Research on Cancer, 1989:113-24. 37. Melkert PWJ, Hopman E, van den Brule A, et al. Prevalence of HPV in cytomorphologically normal cervical smears, as determined by the polymerase chain reaction, is age-dependent. I n t J Cancer 1993;53:919-23.
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38. Pao CC, Lin C-Y, Maa J-S, Lai C-H, Wu S-Y, Soong Y-K. Detection of human papillomaviruses in cervicovaginal cells using polymerase chain reaction.J Infect Dis 1990;161:113-5. 39. Schiffman MH. Commentary: recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. J Nat Cancer Inst 1992;84:394-8. 40. Munoz N, Bosch FX, de Sanjose S, et al. The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. IntJ Cancer 1992;52:743-9. 41. Lorincz AT, Reid R,Jenson AB, Greenberg MD, Lancaster W, Kurman RJ. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 1992;79:328-37. 42. Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Englj Med 1992;327: 1272-8. 43. Brinton LA. Epidemiology of cervical cancer--overview. Epidemiology of human papillomavirus and cervical cancer. IARC Scientific Publication 119. Lyon, France: International Agency for Research on Cancer 1992;3-23. 44. Burghardt E, Ostor AG. Site and origin ofsquamous cervical cancer: a histomorphologic study. Obstet Gynecol 1983;62: 117-27. 45. Stern E, Neely PM. Carcinoma and dysplasia of the cervix: a comparison of rates for new and returning populations. Acta Cytol 1963;7:357-61. 46. CuzickJ, Szarewski A, Terry G, et al. Human papillomavirus testing in primary cervical screening. Lancet 1995;345: 1533-6. 47. Saito K, Saito A, Fu YS, Smotkin D, GuptaJ, Shah IL Topographic study of cervical condyloma and intraepithelial neoplasia. Cancer 1987;59:2064-70.